mGlu 1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits.

Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE

Original Publication: [Cambridge, MA] : Cell Press, c 2012-

Schizophrenic Psychology*; Antipsychotic Agents/*pharmacology ; Behavior, Animal/*drug effects ; Cognition/*drug effects ; Cognitive Dysfunction/*drug therapy ; Excitatory Amino Acid Agonists/*pharmacology ; Glycine/*analogs & derivatives ; Interneurons/*drug effects ; Prefrontal Cortex/*drug effects ; Receptors, Metabotropic Glutamate/*agonists ; Resorcinols/*pharmacology ; Schizophrenia/*drug therapy ; Somatostatin/*metabolism; Animals ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/physiopathology ; Cognitive Dysfunction/psychology ; Disease Models, Animal ; Female ; GABAergic Neurons/drug effects ; GABAergic Neurons/metabolism ; Glycine/pharmacology ; Interneurons/metabolism ; Male ; Memory, Short-Term/drug effects ; Mice, Inbred C57BL ; Mice, Transgenic ; Neural Inhibition/drug effects ; Prefrontal Cortex/metabolism ; Prefrontal Cortex/physiopathology ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/metabolism ; Schizophrenia/metabolism ; Schizophrenia/physiopathology ; Somatostatin/genetics ; Mice ; Rats

Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu 1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu 1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu 1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu 1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu 1 PAM efficacy. Collectively, these findings suggest that mGlu 1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.
Competing Interests: Declaration of interests P.J.C., C.W.L., and C.M.N. received research support from Lundbeck Pharmaceuticals and Boehringer Ingelheim, and C.W.L. also received support from Ono Pharmaceutical during the course of these studies. P.J.C., C.W.L., and C.M.N. are inventors on multiple patents for allosteric modulators for several classes of metabotropic glutamate receptors. The remaining authors declare no competing interests.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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K99 AA027806 United States AA NIAAA NIH HHS; R01 MH119673 United States MH NIMH NIH HHS; R01 NS031373 United States NS NINDS NIH HHS; U54 HD083211 United States HD NICHD NIH HHS; P30 EY008126 United States EY NEI NIH HHS; P30 DK020593 United States DK NIDDK NIH HHS; P30 CA068485 United States CA NCI NIH HHS; P50 HD103537 United States HD NICHD NIH HHS; R37 NS031373 United States NS NINDS NIH HHS; U24 DK059637 United States DK NIDDK NIH HHS; P30 DK058404 United States DK NIDDK NIH HHS; T32 MH065215 United States MH NIMH NIH HHS

Keywords: NMDA receptor hypofunction; cognitive deficits; excitation-inhibition balance; inhibitory transmission; mGlu(1); metabotropic glutamate receptor; prefrontal cortex; schizophrenia; somatostatin interneurons; working memory

0 (Antipsychotic Agents)
0 (Excitatory Amino Acid Agonists)
0 (Receptors, Metabotropic Glutamate)
0 (Resorcinols)
0 (metabotropic glutamate receptor type 1)
51110-01-1 (Somatostatin)
5YR2N37E6D (3,5-dihydroxyphenylglycine)
TE7660XO1C (Glycine)

Date Created: 20211103 Date Completed: 20220215 Latest Revision: 20240923

20240923

PMC8628371

10.1016/j.celrep.2021.109950

34731619